Perinatal Arterial Stroke Treated With Stromal Cells Intranasally

NCT ID: NCT03356821

Last Updated: 2024-05-13

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

10 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-02-11

Study Completion Date

2021-07-27

Brief Summary

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This study will assess safety and feasibility of bone marrow-derived allogeneic MSCs, administered by the nasal route, in neonates who suffered from PAIS.

Detailed Description

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Perinatal arterial ischemic stroke (PAIS) is an important perinatal cause of long-lasting neurodevelopmental problems. Recent studies report an incidence of PAIS of 1 per 2300 full-term infants born alive. Adverse consequences of PAIS include hemiplegia, cognitive dysfunction, epilepsy and speech problems. In 50-75% of infants, neonatal stroke leads to abnormal neuromotor and -developmental outcome or epilepsy. The estimated annual mortality rate of neonatal stroke is 3.49/100,000 annually. Current treatment options for PAIS mainly focus on controlling convulsions and associated infections. There is no treatment available that leads to reduction of neonatal brain damage in this severely affected group of infants. This leads to life-long consequences of PAIS and forms a large burden for patients and society. The overall aim of this project is to meet this need by developing a cell based treatment strategy. Animal models of neonatal brain injury provide evidence for the feasibility and efficacy of intranasal mesenchymal stromal cell (MSC) application in the treatment of PAIS. Additionally, results from human trials with MSCs in the treatment of adult stroke or other pathologic conditions provide evidence that MSC treatment is safe. This project aims at making the first step towards clinical application of MSCs to treat PAIS. Successful completion of this project will provide the first evidence of the safety and feasibility of MSCs to treat brain damage in newborn infants. This study will assess safety and feasibility of bone marrow-derived allogeneic MSCs, administered by the nasal route, in neonates who suffered from PAIS.

Conditions

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Perinatal Arterial Ischemic Stroke Neonatal Stroke

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

A phase I/II, open-label, single-arm, single-center intervention study in the NICU at the Wilhelmina children's Hospital / University Medical Centre in Utrecht of (near-)term newborns ≥36 weeks of gestation within the first week of onset of presenting clinical symptoms.
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Mesenchymal Stem Cells

All (near-)term newborns ≥36 weeks of gestation with or without clinical symptoms of PAIS but with a magnetic resonance imaging (MRI) confirmed PAIS (in the Middle Cerebral Artery region) will be eligible for this study. Following written parental consent, 10 patients will be included in our study.

Group Type EXPERIMENTAL

Mesenchymal Stem Cells

Intervention Type BIOLOGICAL

One dose of 50x10\^6 bone marrow-derived allogeneic MSCs via the nasal route as soon as possible after confirmation of the stroke (in the middle cerebral artery), but within the first week of onset of presenting clinical symptoms. Within 30 minutes after cleaning the nose with saline, using standard procedures operative at the Neonatal Intensive Care Unit, the MSC will be delivered.

Interventions

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Mesenchymal Stem Cells

One dose of 50x10\^6 bone marrow-derived allogeneic MSCs via the nasal route as soon as possible after confirmation of the stroke (in the middle cerebral artery), but within the first week of onset of presenting clinical symptoms. Within 30 minutes after cleaning the nose with saline, using standard procedures operative at the Neonatal Intensive Care Unit, the MSC will be delivered.

Intervention Type BIOLOGICAL

Other Intervention Names

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Bone Marrow-derived Allogeneic Mesenchymal Cells

Eligibility Criteria

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Inclusion Criteria

* (Near-)Term infants, ≥36+0 weeks of gestation, admitted to one of the Dutch Neonatal Intensive Care Units, diagnosed with PAIS, confirmed by MRI within 3 days after presentation with clinical symptoms.
* PAIS as characterized by a predominantly unilateral ischemic lesion within the territory of the middle cerebral artery, with involvement of the corticospinal tracts, cortex, white matter and basal ganglia.
* Written informed consent from custodial parent(s).

Exclusion Criteria

* Any proven or suspected congenital anomaly, chromosomal disorder, metabolic disorder.
* Presence of an infection of the central nervous system.
* No realistic prospect of survival, (e.g. severe brain injury), at the discretion of the attending physician.
Maximum Eligible Age

10 Days

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role collaborator

M.D. Anderson Cancer Center

OTHER

Sponsor Role collaborator

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role collaborator

UMC Utrecht

OTHER

Sponsor Role lead

Responsible Party

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dr. M.J.N.L. Benders

MD, PhD

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Manon Benders, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Floris Groenendaal, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Frank van Bel, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Cora Nijboer, PhD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Locations

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Wilhelmina Childrens Hostpital/University Medical Center Utrecht

Utrecht, , Netherlands

Site Status

Countries

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Netherlands

References

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Donega V, van Velthoven CT, Nijboer CH, Kavelaars A, Heijnen CJ. The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment. J Cereb Blood Flow Metab. 2013 May;33(5):625-34. doi: 10.1038/jcbfm.2013.3. Epub 2013 Feb 13.

Reference Type BACKGROUND
PMID: 23403379 (View on PubMed)

Donega V, van Velthoven CT, Nijboer CH, van Bel F, Kas MJ, Kavelaars A, Heijnen CJ. Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement. PLoS One. 2013;8(1):e51253. doi: 10.1371/journal.pone.0051253. Epub 2013 Jan 3.

Reference Type BACKGROUND
PMID: 23300948 (View on PubMed)

Donega V, Nijboer CH, van Tilborg G, Dijkhuizen RM, Kavelaars A, Heijnen CJ. Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury. Exp Neurol. 2014 Nov;261:53-64. doi: 10.1016/j.expneurol.2014.06.009. Epub 2014 Jun 16.

Reference Type BACKGROUND
PMID: 24945601 (View on PubMed)

Donega V, Nijboer CH, Braccioli L, Slaper-Cortenbach I, Kavelaars A, van Bel F, Heijnen CJ. Intranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions. PLoS One. 2014 Nov 14;9(11):e112339. doi: 10.1371/journal.pone.0112339. eCollection 2014.

Reference Type BACKGROUND
PMID: 25396420 (View on PubMed)

van Velthoven CT, Kavelaars A, Heijnen CJ. Mesenchymal stem cells as a treatment for neonatal ischemic brain damage. Pediatr Res. 2012 Apr;71(4 Pt 2):474-81. doi: 10.1038/pr.2011.64. Epub 2012 Feb 8.

Reference Type BACKGROUND
PMID: 22430383 (View on PubMed)

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell transplantation changes the gene expression profile of the neonatal ischemic brain. Brain Behav Immun. 2011 Oct;25(7):1342-8. doi: 10.1016/j.bbi.2011.03.021. Epub 2011 Apr 5.

Reference Type BACKGROUND
PMID: 21473911 (View on PubMed)

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage. Pediatr Res. 2010 Nov;68(5):419-22. doi: 10.1203/PDR.0b013e3181f1c289.

Reference Type BACKGROUND
PMID: 20639794 (View on PubMed)

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function. J Neurosci. 2010 Jul 14;30(28):9603-11. doi: 10.1523/JNEUROSCI.1835-10.2010.

Reference Type BACKGROUND
PMID: 20631189 (View on PubMed)

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2010 Mar;24(3):387-93. doi: 10.1016/j.bbi.2009.10.017. Epub 2009 Oct 31.

Reference Type BACKGROUND
PMID: 19883750 (View on PubMed)

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Regeneration of the ischemic brain by engineered stem cells: fuelling endogenous repair processes. Brain Res Rev. 2009 Jun;61(1):1-13. doi: 10.1016/j.brainresrev.2009.03.003. Epub 2009 Apr 5.

Reference Type BACKGROUND
PMID: 19348860 (View on PubMed)

Wagenaar N, Nijboer CH, van Bel F. Repair of neonatal brain injury: bringing stem cell-based therapy into clinical practice. Dev Med Child Neurol. 2017 Oct;59(10):997-1003. doi: 10.1111/dmcn.13528. Epub 2017 Aug 8.

Reference Type BACKGROUND
PMID: 28786482 (View on PubMed)

Wagenaar N, de Theije CGM, de Vries LS, Groenendaal F, Benders MJNL, Nijboer CHA. Promoting neuroregeneration after perinatal arterial ischemic stroke: neurotrophic factors and mesenchymal stem cells. Pediatr Res. 2018 Jan;83(1-2):372-384. doi: 10.1038/pr.2017.243. Epub 2017 Nov 1.

Reference Type BACKGROUND
PMID: 28949952 (View on PubMed)

Wagenaar N, Baak LM, van der Aa NE, Groenendaal F, Dudink J, Tataranno ML, Koopman C, Verhage CH, Eijsermans RMJC, van Teeseling HC, Smit LS, Jellema RK, de Haan TR, Ter Horst HJ, de Boode WP, Steggerda SJ, Mulder-de Tollenaer SM, Dijkman KP, de Haar CG, de Vries LS, van Bel F, Heijnen CJ, Nijboer CH, Benders MJNL. Perinatal Arterial Stroke Treated With Stromal Cells Intranasally: 2-Year Safety and Neurodevelopment. Stroke. 2025 Sep;56(9):2410-2418. doi: 10.1161/STROKEAHA.125.050786. Epub 2025 Jul 14.

Reference Type DERIVED
PMID: 40654084 (View on PubMed)

Baak LM, Wagenaar N, van der Aa NE, Groenendaal F, Dudink J, Tataranno ML, Mahamuud U, Verhage CH, Eijsermans RMJC, Smit LS, Jellema RK, de Haan TR, Ter Horst HJ, de Boode WP, Steggerda SJ, Prins HJ, de Haar CG, de Vries LS, van Bel F, Heijnen CJ, Nijboer CH, Benders MJNL. Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study. Lancet Neurol. 2022 Jun;21(6):528-536. doi: 10.1016/S1474-4422(22)00117-X.

Reference Type DERIVED
PMID: 35568047 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

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NL59265.000.16

Identifier Type: -

Identifier Source: org_study_id

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